Brexpiprazole, sold under the brand name Rexulti among others, is an
atypical antipsychotic
The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...
. It is a
dopamine D2 receptor partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...
and has been described as a "serotonin–dopamine activity modulator" (SDAM). The drug was approved by the U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) on 10 July 2015, for the treatment of
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
, and as an
adjunctive treatment for
depression.
It has been designed to provide improved efficacy and tolerability (e.g., less
akathisia
Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back a ...
,
restlessness and/or
insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
) over established adjunctive treatments for
major depressive disorder
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
(MDD).
The drug was developed by
Otsuka and
Lundbeck
H. Lundbeck A/S (commonly known simply as Lundbeck) is a Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products are targe ...
, and is considered to be a successor of Otsuka's top-selling atypical antipsychotic
aripiprazole
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...
(Abilify).
It is available as a
generic medication.
Medical uses
Brexpiprazole is approved for the indication of schizophrenia in Canada, United States, Australia, Japan and Europe. In 2019, it was also approved in
Canada
Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by tot ...
as adjunctive treatment in
Major Depressive Disorder. In 2020 it was approved in
Brazil
Brazil ( pt, Brasil; ), officially the Federative Republic of Brazil (Portuguese: ), is the largest country in both South America and Latin America. At and with over 217 million people, Brazil is the world's fifth-largest country by area ...
only as an adjunctive to the treatment of
Major Depressive Disorder. In the United States it was extended approval for
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
in 2022 in the treatment of pediatric patients from age 13 to 17.
Side effects
The most common adverse events associated with brexpiprazole (all doses of brexpiprazole cumulatively greater than or equal to 5% vs. placebo) were
upper respiratory tract infection
An upper respiratory tract infection (URTI) is an illness caused by an acute infection, which involves the upper respiratory tract, including the nose, sinuses, pharynx, larynx or trachea. This commonly includes nasal obstruction, sore thro ...
(6.9% vs. 4.8%),
akathisia
Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back a ...
(6.6% vs. 3.2%),
weight gain
Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition.
Description
Weight gain occurs w ...
(6.3% vs. 0.8%), and
nasopharyngitis (5.0% vs. 1.6%).
Interactions
Based on information given on the consent forms, it seems brexpiprazole is a substrate of
CYP2D6
Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.
CYP2D ...
and
CYP3A4, like its predecessor
aripiprazole
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...
. Participants in the clinical trials are advised to avoid
grapefruit,
Seville oranges
Seville (; es, Sevilla, ) is the capital and largest city of the Spanish autonomous community of Andalusia and the province of Seville. It is situated on the lower reaches of the River Guadalquivir, in the southwest of the Iberian Peninsula. ...
and related citruses.
Pharmacology
Pharmacodynamics
Brexpiprazole acts as a
partial agonist
In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...
of the
serotonin 5-HT1A receptor and the
dopamine D2 and
D3 receptors.
Partial agonists have both blocking properties and stimulating properties at the receptor they bind to. The ratio of blocking activity to stimulating activity determines a portion of its clinical effects. Brexpiprazole has more blocking and less stimulating activity at the dopamine receptors than its predecessor,
aripiprazole
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...
, which may decrease its risk for agitation and restlessness.
Specifically, where aripiprazole has an intrinsic activity or agonist effect at the
D2 receptor of 60%+, brexpiprazole has an intrinsic activity at the same receptor of about 45%. For aripiprazole, this means more dopamine receptor activation at lower doses, with blockade being reached at higher doses, whereas brexpiprazole is the opposite. By contrast, brexpiprazole has a much higher affinity for the
5-HT1A receptor, potent antagonist at 5-HT2A receptors, and a potent partial agonist at dopamine D2 receptors with lower intrinsic activity compared to
aripiprazole
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...
. In vivo characterization of brexpiprazole shows that it may act as a near-full agonist of the
5-HT1A receptor. This may further underlie a lower potential than aripiprazole to cause treatment-emergent, movement-related disorders such as akathisia due to the downstream dopamine release that is triggered by
5-HT1A receptor agonism. It is also an
antagonist of the serotonin
5-HT2A,
5-HT2B, and
5-HT7 receptors, which may contribute to antidepressant effect. It also binds to and blocks the
α1A-,
α1B-,
α1D-, and
α2C-adrenergic receptors.
The drug has negligible
affinity
Affinity may refer to:
Commerce, finance and law
* Affinity (law), kinship by marriage
* Affinity analysis, a market research and business management technique
* Affinity Credit Union, a Saskatchewan-based credit union
* Affinity Equity Par ...
for the
muscarinic acetylcholine receptor
Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...
s, and hence has no
anticholinergic
Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system.
These agents inhibit the parasympathetic nervous sys ...
effects.
Although brexpiprazole has less affinity for
H1 compared to
aripiprazole
Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...
, weight gain can occur.
History
Partnership with Lundbeck
In November 2011,
Otsuka Pharmaceutical
(), abbreviated OPC, is a pharmaceutical company headquartered in Tokyo, Osaka and Naruto, Japan. The company was established August 10, 1964.
History
OPC's parent company Otsuka Holdings Co. Ltd. joined the Tokyo Stock Exchange through an ini ...
and
Lundbeck
H. Lundbeck A/S (commonly known simply as Lundbeck) is a Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products are targe ...
announced a global alliance. Lundbeck gave Otsuka an upfront payment of $200 million, and the deal includes development, regulatory and sales payments, for a potential total of $1.8 billion.
Specifically for OPC-34712, Lundbeck will obtain 50% of net sales in Europe and Canada and 45% of net sales in the US from Otsuka.
Clinical trials
Brexpiprazole was in clinical trials for adjunctive treatment of
MDD,
adult ADHD,
bipolar disorder
Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...
and
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
.
Major depression
=Phase II
=
The Phase II multicenter, double-blind, placebo-controlled study randomized 429 adult MDD patients who exhibited an inadequate response to one to three approved antidepressant treatments (ADTs) in the current episode. The study was designed to assess the efficacy and safety of brexpiprazole as an adjunctive treatment to standard antidepressant treatment. The antidepressants included in the study were
desvenlafaxine,
escitalopram
Escitalopram, sold under the brand names Lexapro and Cipralex, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. Escitalopram is mainly used to treat major depressive disorder and generalized anxiet ...
,
fluoxetine,
paroxetine
Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...
,
sertraline
Sertraline, sold under the brand name Zoloft among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. The efficacy of sertraline for depression is similar to that of other antidepressants, and the differ ...
, and
venlafaxine
Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic ...
.
=Phase III
=
A new Phase III study was in the recruiting stage: "Study of the Safety and Efficacy of Two Fixed Doses of OPC-34712 as Adjunctive Therapy in the Treatment of Adults With Major Depressive Disorder (the Polaris Trial)".
Its goal is "to compare the effect of brexpiprazole to the effect of placebo (an inactive substance) as add on treatment to an assigned FDA approved antidepressant treatment (ADT) in patients with
major depressive disorder
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...
who demonstrate an incomplete response to a prospective trial of the same assigned FDA approved ADT". Estimated enrollment was 1250 volunteers.
ADHD
* Attention Deficit/Hyperactivity Disorder (STEP-A)
Schizophrenia
=Phase I
=
* Trial to Evaluate the Effects of OPC-34712 (brexpiprazole) on QT/QTc in Subjects With Schizophrenia or Schizoaffective Disorder
=Phase II
=
* A Dose-finding Trial of OPC-34712 in Patients With Schizophrenia
=Phase III
=
* Efficacy Study of OPC-34712 in Adults With Acute Schizophrenia (BEACON)
* Study of the Effectiveness of Three Different Doses of OPC-34712 in the Treatment of Adults With Acute Schizophrenia (VECTOR)
* A Long-term Trial of OPC-34712 in Patients With Schizophrenia
Conferences
* Phase II results were presented at the American Psychiatric Association's 2011 annual meeting in May 2011.
* The drug has been presented at the 2nd Congress of Asian College of Neuropsychopharmacology in September 2011.
* At the US Psychiatric and Mental Health Congress in November 2011 in Vegas, Robert McQuade presented the Phase II Trial results for Schizophrenia
Society and culture
Legal status
In January 2018, it was approved for the treatment of
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
in Japan.
Patents
*
* WIPO PCT/JP2006/317704
* Canadian patent: 2620688
Research
Brexpiprazole was under development for the treatment of
attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
(ADHD) as an
adjunct to
stimulants, but was discontinued for this indication.
It reached
phase 2 clinical trial
Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...
s for this use prior to discontinuation.
References
Further reading
*
External links
*
*
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